This invention relates to processes for making spirolactone compounds of formula I. The process involves ortho lithiation of an aromatic compound followed by subsequent addition to a ketone derivative. After acidification, the desired spirolactone derivative is isolated in good yield. A stereoselective reduction of the ketone intermediate generates the desired cis isomer of the alcohol which is subsequently activated and treated with cyanide to form the desired nitrile intermediate. Hydrolysis of the nitrile under acidic conditions selectively generates the trans carboxylic acid product. Crystallization of the carboxylic acid intermediate gives the desired material in highly pure form.
By this invention, there is provided a process for the preparation of a compound of structural formula I: 
comprising the steps of:
a. Combining a strong base with phenyl isonicotinamide in an aprotic solvent;
b. Adding a protected ketone;
c. Adjusting the pH with an acid to between 1 and 4 to deprotect the ketone;
d. Treating the ketone with a reducing agent to provide an alcohol;
e. Activating the alcohol to make a leaving group;
f. Displacing the leaving group with cyanide to produce a nitrile;
g. Hydrolyzing the nitrile with aqueous acid to yield the compound of formula I.
By this invention, there is provided a process for the preparation of a compound of structural formula I: 
comprising combining a strong base with phenyl isonicotinamide in an aprotic solvent.
A variety of strong bases can be used in the present invention. In one class of the invention, the strong bases include, but are not limited to n-BuLi, sec-BuLi, t-BuLi, LiHMDS, NaHMDS, KHMDS and LiTMP. In a subclass of the invention, the strong base is n-BuLi.
Various aprotic solvents can be used in the present invention. In one class of the invention, the aprotic solvents include, but are not limited to THF, toluene, heptane, dimethoxyethane, benzene, and hexane, diethyl ether, xylene, and any mixtures thereof. In a subclass of the invention the aprotic solvent is THF.
In one class of the invention, the combination of the strong base and the phenyl isonicotinamide, and the addition of the ketone protecting group are run between xe2x88x9278xc2x0 C. and 0xc2x0 C.
The invention is also directed to a process comprising adding a protected ketone after combining a compound of formula I with a strong base and phenyl isonicotinamide in an aprotic solvent.
In one class of the invention, the protected ketone includes, but is not limited to 1,4-cyclohexanedione-mono-ethylene ketal, dimethyl ketal, diethyl ketal, or 1,3 dithiane, and olefin.
The invention is also directed to a process comprising adjusting the pH with an acid to between 1 and 4 to deprotect the ketone.
In one class of the invention, the pH range includes, but are not limited to 2-3. In a subclass of the invention, the pH is 2.40.
In one class of the invention, the acids used to lower the pH include, but are not limited to hydrochloric, sulfuric, phosphoric, or triflic.
The invention is also directed to a process comprising treating the ketone with a reducing agent to provide an alcohol.
In one class of the invention, the reducing agent includes, but is not limited to sodium borohydride, lithium aluminum hydride, or DIBAL. In another class of the invention, the ketone may be reduced via catalytic hydrogenation.
The invention is also directed to a process comprising activating the alcohol to make a leaving group. By activating the alcohol, the alcohol is converted into a leaving group at that carbon.
In one class of the invention, the leaving group includes, but is not limited to mesylate, tosylate, triflate, and halide.
The invention is also directed to a process comprising displacing the leaving group with cyanide to produce a nitrile.
In one class of the invention the cyanide is selected from the group consisting of sodium cyanide, KCN, ZnCN2, and TMSCN.
The invention is also directed to a process comprising hydrolyzing the nitrile with aqueous acid to produce the compound of formula I. The hydrolyzation liberates the free acid.
In one class of the invention, the aqueous acid includes, but is not limited to sulfuric, hydrochloric, phosphoric, and any mixtures thereof.